rs61736451

Variant names:

• chr3-10359892-C-T
• rs61736451
• NM_001001331.4:c.1891G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-10359892-C-T
• chr3-10359892-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001001331.4(ATP2B2):​c.1891G>A​(p.Val631Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00943 in 1,614,226 control chromosomes in the GnomAD database, including 143 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0079 (17 hom., cov: 33)
  • Exomes 𝑓: 0.0096 (126 hom.)
• Consequence: ATP2B2 NM_001001331.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.19
• Publications: 20 publications found

Genes affected

ATP2B2 (HGNC:815): (ATPase plasma membrane Ca2+ transporting 2) The protein encoded by this gene belongs to the family of P-type primary ion transport ATPases characterized by the formation of an aspartyl phosphate intermediate during the reaction cycle. These enzymes remove bivalent calcium ions from eukaryotic cells against very large concentration gradients and play a critical role in intracellular calcium homeostasis. The mammalian plasma membrane calcium ATPase isoforms are encoded by at least four separate genes and the diversity of these enzymes is further increased by alternative splicing of transcripts. The expression of different isoforms and splice variants is regulated in a developmental, tissue- and cell type-specific manner, suggesting that these pumps are functionally adapted to the physiological needs of particular cells and tissues. This gene encodes the plasma membrane calcium ATPase isoform 2. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ATP2B2 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal dominant 82

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• neurodevelopmental disorder

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00996235).
• BP6: Variant 3-10359892-C-T is Benign according to our data. Variant chr3-10359892-C-T is described in ClinVar as Benign. ClinVar VariationId is 17801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00788 (1200/152356) while in subpopulation AMR AF = 0.028 (428/15306). AF 95% confidence interval is 0.0258. There are 17 homozygotes in GnomAd4. There are 604 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1200 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001001331.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2B2	NM_001001331.4	MANE Select	c.1891G>A	p.Val631Met	missense	Exon 13 of 23	NP_001001331.1	Q01814-1
	ATP2B2	NM_001438646.1		c.1798G>A	p.Val600Met	missense	Exon 11 of 21	NP_001425575.1
	ATP2B2	NM_001353564.1		c.1756G>A	p.Val586Met	missense	Exon 11 of 21	NP_001340493.1	Q01814-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2B2	ENST00000360273.7	TSL:5 MANE Select	c.1891G>A	p.Val631Met	missense	Exon 13 of 23	ENSP00000353414.2	Q01814-1
	ATP2B2	ENST00000452124.2	TSL:1	c.1798G>A	p.Val600Met	missense	Exon 10 of 20	ENSP00000414854.2	Q01814-8
	ATP2B2	ENST00000397077.6	TSL:1	c.1756G>A	p.Val586Met	missense	Exon 10 of 20	ENSP00000380267.1	Q01814-6

Frequencies

GnomAD3 genomes AF: 0.00784 AC: 1193 AN: 152238 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.00289

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0274

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00883

Gnomad OTH AF: 0.00716

GnomAD2 exomes AF: 0.0115 AC: 2877 AN: 250766 AF XY: 0.0104

Gnomad AFR exome AF: 0.00252

Gnomad AMR exome AF: 0.0477

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00171

Gnomad NFE exome AF: 0.00840

Gnomad OTH exome AF: 0.0103

GnomAD4 exome AF: 0.00960 AC: 14027 AN: 1461870 Hom.: 126 Cov.: 31 AF XY: 0.00926 AC XY: 6731 AN XY: 727238

African (AFR) AF: 0.00164 AC: 55 AN: 33480

American (AMR) AF: 0.0457 AC: 2043 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000306 AC: 8 AN: 26136

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39700

South Asian (SAS) AF: 0.00391 AC: 337 AN: 86256

European-Finnish (FIN) AF: 0.00125 AC: 67 AN: 53410

Middle Eastern (MID) AF: 0.00364 AC: 21 AN: 5768

European-Non Finnish (NFE) AF: 0.00989 AC: 10999 AN: 1112004

Other (OTH) AF: 0.00813 AC: 491 AN: 60396

GnomAD4 genome AF: 0.00788 AC: 1200 AN: 152356 Hom.: 17 Cov.: 33 AF XY: 0.00811 AC XY: 604 AN XY: 74500

African (AFR) AF: 0.00289 AC: 120 AN: 41586

American (AMR) AF: 0.0280 AC: 428 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00414 AC: 20 AN: 4830

European-Finnish (FIN) AF: 0.00122 AC: 13 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00882 AC: 600 AN: 68030

Other (OTH) AF: 0.00709 AC: 15 AN: 2116

Alfa AF: 0.00804 Hom.: 13

Bravo AF: 0.00967

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00721 AC: 62

ExAC AF: 0.00881 AC: 1069

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00938

EpiControl AF: 0.00717

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Agenesis of the corpus callosum with peripheral neuropathy (1)
-	-	1	ATP2B2-related disorder (1)
-	-	1	Deafness, autosomal recessive 12, modifier of (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.2
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.86	N
REVEL	Uncertain	0.34
Sift	Benign	0.24	T
Sift4G	Benign	0.16	T
Polyphen		0.85	P
Vest4		0.40
MPC		1.8
ClinPred		0.012	T
GERP RS		4.9
Varity_R		0.17
gMVP		0.83
Mutation Taster		=78/22	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs61736451; hg19: chr3-10401576; COSMIC: COSV108189186;